The insulin-like growth factors (IGFs) are clearly involved in maintaining and stimulating breast tumor cell growth, and are therefore potential targets for therapeutic attack in the treatment of breast cancer. The IGF system comprises several elements: two growth factors (IGF-I and IGF-II), two receptors (IGFRI and IGFRII) of which the first may mediate the growth- stimulating actions of IGF-I and IGF-II, and at least five IGF binding proteins (IGFBPs), which may either enhance or interfere with tumor growth stimulation. In order to target the IGF system effectively, it will be necessary to define the key elements of the system involved in growth regulation, as well as to demonstrate that specifically attacking these elements can inhibit breast cancer growth. We therefore propose three specific aims: (1) To inhibit IGF-stimulated breast cancer cell growth by blocking the expression of the IGFRI using antisense strategies; (2) To define the role of IGFRII in breast cancer cell growth by both inhibiting the receptor (using anti-sense strategies) and over-expressing it (using inducible promoters), and to determine the effects of these manipulations on basal and IGF-stimulated growth; (3) To investigate the expression and function of the IGF binding proteins (IGFBPs) in breast cancer cells and clinical breast tumor specimens. It is well established that polypeptide growth factors are important regulators of cancer cell growth in vitro and that interference with growth factor pathways can lead to inhibition of tumor proliferation in many different model systems. This proposal therefore seeks to fully characterize the cellular effectors (receptors and binding proteins) of the IGF system, and to use these observations to develop feasible therapeutic strategies for inhibiting IGF-mediated breast cancer proliferation.